Advances in microfluidics technology are revolutionizing molecular biology procedures for enzymatic analysis (e.g., glucose and lactate assays), DNA analysis (e.g., polymerase chain reaction and high-throughput sequencing), and proteomics. The basic idea of microfluidic biochips is to integrate assay operations such as detection, sample pre-treatment and sample preparation on a single microchip. An emerging application area for biochips is clinical pathology, especially the immediate point-of-care diagnosis of diseases. In addition, microfluidics-based devices, capable of continuous sampling and real-time testing of air/water samples for biochemical toxins and other dangerous pathogens, can serve as an always-on “bio-smoke alarm” for early warning. Low flow separation techniques, such as capillary electrophoresis, capillary electrochromatograghy, and low flow HPLC are further emerging applications.
A lab-on-a-chip (LOC) is a device that integrates one or several laboratory functions on a single chip of only millimeters to a few square centimeters in size. LOCs deal with the handling of extremely small fluid volumes down to less than pico liters. Lab-on-a-chip devices are a subset of Microelectromechanical Systems (MEMS) devices and are often indicated by “Micro Total Analysis Systems” (μTAS) as well. Microfluidics is a broad term that includes mechanical flow control devices like pumps, valves and sensors such as flow meters and viscometers. “Lab-on-a-Chip” generally relates to the scaling of single or multiple lab processes down to chip-format, whereas “μTAS” is dedicated to the integration of the total sequence of lab processes to perform chemical analysis.
μTAS technologies are suitable for applications other than just analysis. For example, channels (capillary connections), mixers, valves, pumps and dosing devices are all suitable μTAS technologies.
The first LOC analysis system was a gas chromatograph, developed in 1975 by S. C. Terry—Stanford University. However, it was not until the end of the 1980's, and beginning of the 1990's, that LOC research started to seriously grow. The development of micropumps, flow sensors and the concepts for integrated fluid treatments for analysis systems was spurred by this research. These μTAS concepts demonstrated that integration of pre-treatment steps, usually done at lab-scale, could extend the simple sensor functionality towards a complete laboratory analysis, including additional cleaning and separation steps.
A big boost in research and commercial interest came in the mid 1990's, when μTAS technologies turned out to provide interesting tooling for genomics applications such as capillary electrophoresis and DNA microarrays. Another boost in research support came from the military, especially from DARPA (Defense Advanced Research Projects Agency), for their interest in portable bio/chemical warfare agent detection systems. The added value was not only limited to integration of lab processes for analysis but also the characteristic possibilities of individual components and the application to other, non-analysis, lab processes. Hence the term “Lab-on-a-Chip” was introduced.
Although the application of LOCs is still novel and modest, a growing interest of companies and applied research groups is observed in different fields such as analysis (e.g. chemical analysis, environmental monitoring, medical diagnostics and cellomics) but also in synthetic chemistry (e.g. rapid screening and microreactors for pharmaceutics). Further application developments, research in LOC systems is expected to extend towards downscaling of fluid handling structures as well, by using nanotechnology. Sub-micrometer and nano-sized channels, DNA labyrinths, single cell detection analysis and nano-sensors are feasible for interaction with biological species and large molecules.
Despite the immense amount of research around creating the chips themselves, interfacing to the real world, the “Chip-to-World” interface technology, has been limited. Progress to interface to the LOCs has progressed slowly. This invention serves as a means to make connections to microchips and similar-based microfluidic devices.
Lab-on-a-chip technology may be used to improve global health, particularly through the development of point-of-care testing devices. In countries with few healthcare resources, infectious diseases that would be treatable in a developed nations are often deadly. In some cases, poor healthcare clinics have the drugs to treat a certain illness but lack the diagnostic tools to identify patients who should receive the drugs. LOC technology may be the key to provide powerful new diagnostic instruments. The goal of these researchers is to create microfluidic chips that will allow healthcare providers in poorly equipped clinics to perform diagnostic tests such as immunoassays and nucleic acid assays without additional laboratory support.
The basis for most LOC fabrication processes is photolithography. Initially most processes were in silicon, as these well-developed technologies were directly derived from semiconductor fabrication. Because of demands for e.g. specific optical characteristics, bio- or chemical compatibility, lower production costs and faster prototyping, new processes have been developed such as glass, ceramics and metal etching, deposition and bonding, PDMS processing (e.g., soft lithography), thick-film- and stereolithography as well as fast replication methods via electroplating, injection molding and embossing. Furthermore, the LOC field more and more exceeds the borders between lithography-based microsystem technology, nanotechnology and precision engineering.
LOCs may provide advantages, which are specific to their application. Typical advantages of LOC systems include:                low fluid volumes consumption (less waste, lower reagents costs and less required sample volumes for diagnostics);        faster analysis and response times due to short diffusion distances, fast heating, high surface to volume ratios, small heat capacities;        better process control because of a faster response of the system (e.g. thermal control for exothermic chemical reactions);        compactness of the systems due to integration of much functionality and small volumes;        massive parallelization due to compactness, which allows high-throughput analysis;        lower fabrication costs, allowing cost-effective disposable chips, fabricated in mass production; and        safer platform for chemical, radioactive or biological studies because of integration of functionality, smaller fluid volumes and stored energies.        
To interface microchips to their supporting hardware systems remains a significant challenge. And the lack of robust, reliable technology to make these connections has not only slowed microfluidic research, but is preventing chip-based solutions from being applied to real world applications. While extensive research effort has been directed toward microchip performance and fabrication, very little effort has been focused on technologies to interface these chips to fluidic and electronic hardware. The end result is that microchip performance is often compromised due to the underdeveloped interface technology.
One method to make a fluidic connection to a chip is by use of a custom housing to clamp the connection. In FIGS. 1A-1B there is shown a custom made housing 10 to effect a connection. A microchip 11 rests in a bottom plate 12, the bottom plate being specifically designed to house the microchip 11. Fittings 13 are attached to the top plate 14, the fittings 13 being designed to effect a fluidic connection to the microchip. A gasket 15 is placed between the fittings 13 and the channel port 16 in microchip 11. The top plate 14 is then placed on the bottom plate 12 and the screws 17 are threaded into the threaded receiver 18 to compress the gasket 15 as shown in FIG. 1B. The problem with clamping systems is that the housing must be custom made for each microchip design. Also, this approach seals all fittings on the microchip, offering no independent control. Furthermore, the sealing plate may block the view or access to regions of interest on the microfluidic device. This approach is also problematic for large surfaces as the plate must be sufficiently rigid and thick to provide ample sealing force, and over a large surface area the sealing force would vary too greatly to create an effective seal.
The most common approach for making connections between fluidic sources and chip-based devices is the manual process of adhesion or “gluing” of polymer fittings or wells to the ports on a chip. In FIGS. 2A-2C there is shown a fitting being bonded to a microchip. An adhesive 21 is placed around the opening on the microchip 22. A fitting 23 having a gasket 24 is then pressed onto the adhesive 21. Clamps 25 are then attached to the fitting 23 to compress the adhesive 21 while it dries. This is a time consuming process that requires extreme skill on the part of the user. Furthermore, the adhesive may leach into the fluid, thereby contaminating the system. Over time the adhesive degrades and the fitting may develop leaks. This conventional process has many drawbacks including: the connections are permanent, it is a labor and time intensive process, it is only amenable to certain substrate materials, and it can not be automated.
Adhesion approaches have additional shortcomings. The process requires exceptional hand-to-eye coordination for both the fitting placement, as well as the subsequent physical clamping of the parts for the drying or curing step. Also, the curing process generally requires heat, so that heat-sensitive material or chemistries cannot be placed in the microchip features prior to adhering the fittings, complicating manufacturing processes. The curing process involves cross-linking of reactive organic species such as epoxies, which slowly leach out of solution following prolonged exposure to solvents. For extremely sensitive analyses, this leaching can lead to false positives in organic detection. Furthermore, the conventional fittings are relatively large in dimension to allow for hand manipulation, however this results in the fittings covering a large amount of precious area on the microchip, affecting the feature densities and the channel architectures. Additionally the large fittings create excessive fluid dead volumes which negatively impact microchip performance and separation quality. The large dead volume also increases the fluid delivery time to the chip. The adhesion approach fatigues overtime, resulting in fluid leakage and subsequent failure of the microchip device. Effective adhesion requires a compatible microchip substrate material. Therefore when using adhesion, chips cannot be made from certain otherwise desirable materials such as Teflon and polypropylene. When adhered fittings are used, the amount of fluid pressure that a microchip can receive is realistically limited to hundreds of PSI, however HPLC and CEC applications should ideally operate at 1000's of PSI fluid pressure. Consequently if the pressure used is too low, the separation performance is compromised, and if the pressure used is too high, the fitting will detach, leakage will occur, and device failure will result. Even if the device has a plurality of fittings, if a single fitting fatigues or fails, the microchip device may be rendered useless. Adhered fittings are, for practical purposes, permanent and cannot be removed. Adhered fitting connections cannot be made in an automated fashion.
With these limitations of the conventional technology, it is apparent that a novel means of interfacing microchips with their supporting hardware is critically needed. To meet this need, a fluidic probe system capable of making automated, non-permanent, low and high pressure connections to microfluidic chip-based devices without the use of bonding or adhering is used. Connections are made using a compression device equipped with a dynamic force monitoring and compensation mechanism, allowing for precise, robust, repeatable connections. This compensation mechanism ensures leak-free operation, even in the event of temperature cycling or material fatigue. Optionally, the device contains an integrated means of leak sensing.
Therefore, a device that can interface microchips with supporting hardware is desired.
Furthermore, a system that is capable of making high and low pressure fluidic connections to microchips and microfluidic devices is desired.
Even further, a system that can provide electrical potentials to interface optics and external hardware to microchips and devices is desired.